Muscular dystrophies (MDs) are a class of hereditary, degenerative disorders of striated muscles caused by defects in genes that encode a diverse group of proteins. Dystroglycanopathies are a particular subset of MDs that share the same biochemical feature of reduced glycosylation of α-dystroglycan and diminished laminin binding activity. Dystroglycanopathies are the second most commonly occurring group of MDs, second only to Duchenne muscular dystrophy. The different disorders within dystroglycanopathies show a wide spectrum of clinical severities. (Qiao et al. Molecular Therapy doi:10.1038/mt.2014.141; pp 1-10 (Jul. 22, 2014); Blaeser et al. Hum Genet 132:923-934 (2013).
Dystroglycan (DG) consists of a heavily glycosylated extracellular α subunit (α-DG) and a transmembrane β subunit (β-DG). α-DG and β-DG are encoded by a single gene and are post translationally cleaved to generate the two subunits. α-DG is a cell surface receptor for several extracellular matrix proteins including laminin, agrin, and perlecan in muscle, and neurexin in the brain. DG functions as a molecular anchor, connecting the extracellular matrix with the cytoskeleton across the plasma membrane in skeletal muscle. Deficiencies in α-DG post-translational modification is largely responsible for the disorders that make up the dystroglycanopathies. One of the proteins identified to be in the DG glycosylation pathway is fukutin-related protein (FKRP), which is involved in the glycosylation of O-linked mannose in α-DG (Qiao et al. Molecular Therapy doi:10.1038/mt.2014.141 pp 1-10 (Jul. 22, 2014); Blaeser et al. Hum Genet 132:923-934 (2013)).
Mutations in the gene encoding FKRP result in a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. Currently, no effective treatment is known for dystroglycanopathies involving a reduction in glycoslation of α-DG (Xu et al. Mol. Therapy 21:10doi:10.1038/mt.2013.156 (Jul. 2, 2013)).
The present invention overcomes previous shortcomings in the art by providing methods and compositions to treat dystroglycanopathies associated with a deficiency in reduction in glycoslation of α-DG.